Universität zu Köln

Stoeckigt, Florian, Eichhorn, Lars ORCID: 0000-0002-9769-0639, Beiert, Thomas, Knappe, Vincent, Radecke, Tobias, Steinmetz, Martin, Nickenig, Georg, Peeva, Viktoriya, Kudin, Alexei P., Kunz, Wolfram S., Berwanger, Carolin, Kamm, Lisa, Schultheis, Dorothea, Schloetzer-Schrehardt, Ursula, Clemen, Christoph S., Schroeder, Rolf and Schrickel, Jan W. (2020). Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice. PLoS One, 15 (3). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Background Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p. R350P. Methods and results Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 +/- 2.9%, HET-sham: 64.5 +/- 4.7%, WT-TAC: 63.5 +/- 4.9%, HET-TAC: 55.7 +/- 5.4%; p < 0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 +/- 2385 mu l/min, HET sham: 10391 +/- 1349 mu l/min, WT-TAC: 8097 +/- 1903 mu l/min, HET-TAC: 5793 +/- 2517 mu l/min; p< 0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 +/- 406, HET-sham: 13526 +/- 781, WT-TAC: 11155 +/- 3315, HET-TAC: 8649 +/- 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. Conclusion Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stoeckigt, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Eichhorn, Lars UNSPECIFIED orcid.org/0000-0002-9769-0639 UNSPECIFIED Beiert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Knappe, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED Radecke, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinmetz, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Nickenig, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Peeva, Viktoriya UNSPECIFIED UNSPECIFIED UNSPECIFIED Kudin, Alexei P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berwanger, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamm, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Schultheis, Dorothea UNSPECIFIED UNSPECIFIED UNSPECIFIED Schloetzer-Schrehardt, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Clemen, Christoph S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrickel, Jan W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-341481
DOI:	10.1371/journal.pone.0228913
Journal or Publication Title:	PLoS One
Volume:	15
Number:	3
Date:	2020
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DESMIN-MUTATION; MITOCHONDRIAL MORPHOLOGY; DILATED CARDIOMYOPATHY; CALCIUM HOMEOSTASIS; MUTANT DESMIN; MUSCLE; ONSET; VIVO Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34148